tbuckley/cabot-search huggingface dataset:
CNSC-25. NEURAL SIGNATURE OF GBM EXHIBITS SYNAPTOGENIC AND OPC-LIKE FEATURES AND INDEPENDENTLY PREDICTS PATIENT SURVIVAL
Authors: Richard Drexler, Robin Khatri, Thomas Sauvigny, Malte Mohme, Alice Ryba, Lasse Dührsen, Cecile Maire, Amanda Salviano-Silva, Katrin Lamszus, Manfred Westphal, Jens Gempt, Annika Wefers, Julia Neumann, Helena Bode, Fabian Hausmann, Tobias Huber, Stefan Bonn, Daniel Delev, Katharina Weber, Patrick Harter, Julia Onken, Peter Vajkoczy, David Capper, Benedikt Wiestler, Michelle Monje, Dana Silverbush, Volker Hovestadt, Mario Suva, Saritha Krishna, Shawn Hervey-Jumper, Ulrich Schüller, Dieter Henrik Heiland, Sonja Hänzelmann, Franz L Ricklefs
Journal: Neuro-Oncology (2023)

Abstract Interactions of neural cells with glioma cells drive tumor growth. In this study, we identified an epigenetically-defined, malignant neural signature of IDH-wildtype glioblastoma (GBM) that significantly influenced patients’ outcome. We used DNA methylation-based reference signatures of neural cells to deconvolve 1.058 primary patient GBM samples. Samples were classified based on the neural reference signature and annotated as low or high neural GBM. A high neural GBM was linked to hypomethylation of CpG sites associated with invasiveness, neuron-to-glioma-interactions, and transsynaptic signaling. Through spatially resolved, single cell transcriptomic and proteomic profiling, we discovered a correlation between the high neural signature and the upregulation of early development programs in OPC and NPC-like cells. These traits were accompanied by diminished immune infiltration and immunological response, further highlighting the distinctive neural-like nature of GBM. High neural GBM demonstrated increased connectivity as evidenced by magnetoencephalography and resting state magnet resonance imaging. Spatiotemporal tumor sampling showed a homogeneous and stable neural signature in newly diagnosed and recurrent GBM. In newly diagnosed GBM, a high neural signature correlated with decreased survival in 306 patients (median OS 15.0 versus 20.0 months, p&amp;lt; 0.001). Patient-derived xenograft models corroborated the aggressive nature of high neural GBM, showing a significantly reduced median OS of 58 days compared to 73 days (p&amp;lt; 0.01). These high neural GBM xenografts also exhibited an elevated tumor burden and an increase in neuron-glioma synapse formation. Consideration of the extent of resection showed a dependency on the neural subgroup as high neural GBM had an increased benefit from a complete contrast enhancing tumor removal when compared to low neural GBM. As a preoperative biomarker, the concentration of BDNF was increased in serum of high neural GBM patients (p &amp;lt; 0.01). Overall, we present an epigenetically-defined malignant neural signature in GBM that is associated with an unfavorable patient survival.
CTNI-08. TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER-2 POSITIVE BREAST CANCER (TUTOR): A MULTICENTER PHASE 1 CLINICAL TRIAL
Authors: Manmeet Ahluwalia, Ahmad Ozair, Atulya Khosla, Shreyas Bellur, Rupesh Kotecha, Michael McDermott, Minesh Mehta, Ana Sandoval-Leon, Reshma Mahtani, David Peereboom
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND 20-40% of HER-2-positive breast cancer patients develop brain metastases (BMs), which are frequently tackled with stereotactic radiosurgery (SRS). Tucatinib, an oral HER-2 selective tyrosine kinase inhibitor (TKI), has demonstrated efficacy for HER-2-positive breast cancer in combination with capecitabine and trastuzumab. We hypothesize that a combinatorial approach for HER-2 positive breast cancer BMs (BCBM) will lead to better long-term control of BMs and systemic disease. METHODS This is an in-progress, prospective, single-arm, multicenter, phase 1 clinical trial that aims to determine the safety of combination of tucatinib, capecitabine, and trastuzumab with SRS in patients with HER-2 positive BCBM. Patients with age 18-80 years, ECOG 0-2, normal organ function, and up to 10 newly-diagnosed BMs are enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. The primary endpoint of the study is the maximum tolerated dose (MTD) of tucatinib with SRS. This de-escalation study starts tucatinib at a dose level of 300 mg BID. Dose level -1 is 250 mg BID and level -2 is 200 mg BID. Upto 40 patients will be enrolled based on a 3 + 3 design. We plan to expand the cohort at MTD to 40 patients to assess the safety and efficacy of the combination. Secondary endpoints include efficacy as determined by response rate, intracranial PFS, extracranial PFS, and overall survival. Patients are administered oral tucatinib with SRS, followed by oral tucatinib for two weeks which is the dose-limiting toxicity (DLT) period. This is followed by tucatinib, trastuzumab, and capecitabine until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting more than seven days, febrile neutropenia, and any non-hematologic toxicity of grade 3 or greater (excluding alopecia). The trial started enrollment in February 2023. Trial Information: NCT05553522.
DISP-08. UNMET NEEDS: WHAT PEOPLE LIVING WITH GLIOBLASTOMA LACK TODAY, INCLUDING ACCESS TO CRITICAL GENOMIC TUMOR TESTING
Authors: Alice Stebbins, Kelli Duprey, Ed Pilkington, Martha Wilkie
Journal: Neuro-Oncology (2023)

Abstract PURPOSE In 2022 and 2023, the non-profit OurBrainBank asked its community of people living with glioblastoma and care partners about the current state of GBM treatment in the USA including whether the patient received genomic tumor analysis. METHOD: OurBrainBank conducted an online survey in which we posted queries through two Facebook groups: “Glioblastoma — GBM SURVIVORS TO THRIVERS!” and “OurBrainBank GBM Patient &amp; Caregiver Community.” RESULTS More than 100 people responded to the Facebook posts stating the priorities they felt they most needed. Top of the list were faster FDA approval for promising therapies, better treatment for veterans, speedier approval for disability benefits as well as common-sense improvements to Medicare/Medicaid, a stop to unreasonable insurance practices, and more flexibility regarding clinical trials. For the survey, 133 people responded. Of the sample group, 50% reported that they had not been informed about tumor testing and 70% said they were unsure or not informed about storing tumor tissue. For the 30% who knew about storing tissue, only half actually had done so. More than 50% did not know about tumor types or mutations. Only half felt that they received enough information to make educated decisions. Those living in urban areas or able to travel received care at hospitals that specialized in brain tumors, but by contrast people living in rural areas or far from a center of excellence did not. Half of respondents felt that they did not enjoy an equal and collaborative relationship with their medical team. CONCLUSION GBM patients and their caregivers are not treated consistently, particularly in regard to genomic tumor testing, a vital first step toward personalized treatment. Many do not receive optimal care and may not even see a specialist. With a median survival rate of 12-18 months, there is much improvement needed.
CTNI-53. ESTABLISHING A PHASE I AND RANDOMIZED PHASE II TRIAL OF SELINEXOR AND TEMOZOLOMIDE IN GLIOBLASTOMA
Authors: Frances Chow, Michael Berens, Sharon Tamir, Yosef Landesman, Christopher Walker, Joycelynne Palmer, Alyx Porter, David Piccioni, Douglas Ney, Macarena de la Fuente, Sani H Kizilbash, Kimberly Bojanowski-Hoang, Lindsay Lipinski, Roy Strowd, Pierre Giglio, Maya Hrachova, Megan Mantica, David Schiff, Steven Gore, Jana Portnow
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity via tumor suppressor protein nuclear localization and reactivation, oncoprotein translation suppression, and DNA repair inhibition. As a single agent, SEL has demonstrated adequate brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS We developed in vitro and in vivo studies to rationally design a phase I/II trial to evaluate the safety and efficacy of the sequential combination of SEL+TMZ. Sequential treatment of U87 cells and intracranial mouse xenografts demonstrated superior DNA damage (ɣH2A.X, cleaved PARP) and overall survival compared to combination or single-agent therapy (HR 0.25 [95% CI, 0.07-0.84]; p = 0.01, log-rank). We used the top-scoring pair method to identify a 6 gene-pair RNAseq signature associated with response to SEL. RESULTS Based on preclinical findings, we developed and opened a multi-institutional phase I/II clinical trial in October 2022. Eligibility includes histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. Primary objectives are safety and preliminary efficacy. Secondary objectives are overall response rate, efficacy, and prospective validation of a molecular signature of response. Phase I dose finding by IQ 3 + 3 (n = 12) involves TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. Phase II will involve randomization (n = 72) to the RP2D of SEL+TMZ versus monotherapy TMZ. Using proportional hazards regression, RHR 0.5 with p &amp;lt; 0.1 will demonstrate sufficient efficacy. We have enrolled 3 participants in dose level 1 (SEL 60mg) with no dose-limiting toxicities (DLTs) observed. Additional preliminary results will be presented. CONCLUSION Preliminary results suggest that a sequential dosing regimen of SEL+TMZ is feasible and initial dose is well-tolerated and may minimize the cumulative toxicity of SEL. The trial is currently enrolling nationwide (NCI #10505, NCT05432804).
BIOS-05. USING DATA-DRIVEN ANALYTICS TO PREDICT SURVIVAL IN PEDIATRIC PATIENTS WITH MEDULLOBLASTOMA: THE UTILITY OF MACHINE LEARNING IN NEXT-GENERATION NEURO-ONCOLOGY PROGNOSTICATION
Authors: Nolan Brown, Cathleen Kuo, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma is the most common malignant intracranial tumor affecting the pediatric population. Despite advancements in multimodal treatment over the past 2 decades yielding a &amp;gt;75% 5-year survival rate, children who survive often have substantial neurological and cognitive sequelae. We aimed to identify risk factors and develop a clinically friendly online calculator for prognostic estimation in pediatric medulloblastoma patients. Pediatric patients with a histopathologically confirmed diagnosis of medulloblastoma were extracted from the Surveillance Epidemiology and End RESULTS: database (2000-2019) and split into training and validation cohorts in an 80:20 ratio (Figure 1). The Cox proportional hazards model was used to identify the univariate and multivariate survival predictors. Subsequently, a calculator with those factors was developed to predict 2-, 5-, and 10-year overall survival as well as median survival months for pediatric medulloblastoma patients. The performance of the calculator was determined by discrimination, calibration, and decision curve analysis (DCA). A total of 1,739 pediatric patients with medulloblastoma met the prespecified inclusion criteria. Fourteen variables, including age, sex, race, ethnicity, median household income, county attribute, laterality, histology, anatomical location, tumor grade, tumor size, surgery status, radiotherapy, and chemotherapy, were included in the calculator (). The concordance index was 0.757 in the training cohort and 0.762 in the validation cohort, denoting clinically useful predictive accuracy. Good agreement between the predicted and observed outcomes was demonstrated by the calibration plots. The DCA curves indicated that the developed model has a good clinical prognostic benefit for pediatric medulloblastoma patients, and could aid prognostication efforts in the clinical setting. An easy-to-use prognostic calculator for a large cohort of pediatric patients with medulloblastoma was established. Future efforts should focus on improving granularity of population-based registries and externally validating the proposed calculator.
EPCO-44. RHABDOID TUMOR PREDISPOSITION SYNDROME DUE TO A GERMLINE SMARCB1 MUTATION IN TWO INFANT SIBLINGS
Authors: Ana Quintero, Derek Hanson, Helio Pedro, Timothy Vogel
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Rhabdoid tumors (RTs) are highly aggressive malignancies caused by a loss–of–function mutation in the SMARCB1 tumor suppressor gene on chromosome 22 that makes up the SW1/SNF chromatin remodeling complex involved in gene transcription. In rhabdoid tumor predisposition syndrome (RTPS), a biallelic germline SMARCB1 mutation markedly increases the risk of affected individuals developing early, aggressive, and rapidly progressing RTs, most commonly in the CNS, referred to as atypical teratoid rhabdoid tumors (AT/RT), and the kidneys, but oftentimes presents with synchronous lesions. In this case series, we present a family affected by RTPS with a recurrence of AT/RT in two infant siblings with the same germline SMARCB1 mutation. CASE SERIES DESCRIPTION An 8-month-old female was brought to the emergency department for 3 months of vomiting, developmental regression, and CN VI palsy. Brain imaging revealed a posterior fossa mass, acquired obstructive hydrocephalus, and spinal metastasis. Four years later, her 3-month-old sister was also brought in for evaluation for 2 months of vomiting, irritability, increasing head circumference, and vertical gaze palsy. Her brain imaging similarly showed a posterior fossa mass and acquired obstructive hydrocephalus, but no metastasis. Both siblings underwent subtotal tumor resections and ventriculoperitoneal shunt placement followed by chemotherapy. While on active treatment, they experienced rapid disease progression and ultimately succumbed to their illness. Genetic testing on the family identified the same in-frame deletion in the SNF5 homology domain of SMARCB1 and loss of heterozygosity of chromosome 22 in the two sisters; their mother was found to be a carrier. CONCLUSION This case series describes a family affected by RTPS, demonstrating the risk of familial recurrence in SMARCB1 germline mutations and emphasizing the need for genetic testing and counseling for these families should they wish to have additional children.
IMMU-08. EOSINOPHILS ARE IMPORTANT MODULATORS OF AN IMMUNE-RESPONSIVE TUMOR-MICROENVIRONMENT IN GLIOBLASTOMA
Authors: Christel Herold-Mende, Dieter Henrik Heiland, Valentina Fermi, Andreas von Deimling, Andreas Unterberg, Rolf Warta
Journal: Neuro-Oncology (2023)

Abstract Eosinophils, bone marrow-derived granulocytes involved in allergic asthma and autoimmunity, have attracted increasing attention due to their assumed role in effective responses to immune checkpoint blockade in some extracranial tumors. However, the role of this rare type of immune cells in immunologically cold tumors such as glioblastoma (GBM) has not been studied so far. When quantifying immune infiltrates and levels of 30 immune-relevant cytokines in 60 matched pairs of human primary and recurrent GBM, strongest correlations (r= 0.71-0.93) were observed for the eosinophil-associated cytokines Eotaxin and Il-5 as well as for TNFa, IFNg and Il2 which are important cytokines for cytotoxic T cell responses. A combined score of these cytokines (Eo score) turned out to be an independent prognostic marker for improved overall survival of GBM patients. Furthermore, multicolor immunofluorescent staining revealed that Eo score high GBM are significantly higher infiltrated by effector T cells and show a significantly lower infiltration with anti-inflammatory M2-like tumor-associated macrophages / microglia cells (M2-TAM) in recurrent GBM. Flowcytometry analysis of GBM-derived single cell suspensions confirmed a positive correlation of higher eosinophil numbers with higher numbers of tumor-infiltrating T cells, while an inverse relation between eosinophils and monocytes could be demonstrated in the TCGA data set. Spatial transcriptomic data of human GBM confirmed that areas with a higher eosinophil infiltration showed higher numbers of T cells and pro-inflammatory M1-TAM, lower numbers of M2-TAM and a remarkable vessel normalization. Finally, in a newly developed patient-derived GBM organoid model we could corroborate the functional impact of eosinophils on the tumor-microenvironment. An increase of eosinophil numbers in these patient avatars resulted in a significantly decreased number of M2-TAM. Altogether, tumor-infiltrating eosinophils seem to be a novel type of immune-modulator in GBM and may enhance immune responses by shaping the tumor niche from an immunosuppressive to an immunepermissive microenvironment.
NIMG-23. COMBINATION OF ADC MRI AND FET PET FOR THE ASSESSMENT OF QUANTITATIVE TUMOR PRESENCE IN DIFFUSE GLIOMA
Authors: Kaithlyn Tjong Tjin Joe, Pieter Wesseling, Frederik Barkhof, Jeroen Beliën, Maqsood Yaqub, Petra Pouwels, Roel Verhaak, Jaap Reijneveld, Annemieke Rozemuller, Peter Vandertop, Ronald Boellaard, Floris Barthel, Philip de Witt Hamer, Elsmarieke van de Giessen, Niels Verburg
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Local treatment of diffuse glioma is currently guided by standard MRI sequences. Yet, the combination of apparent diffusion coefficient (ADC) and O-(2-[18F]-fluoroethyl)-L-tyrosine positron emission tomography (FET PET) (ADC/FET) detects qualitatively assessed histopathological tumor presence more accurately than standard MRI imaging. It is unknown whether this is similar for quantitatively assessment of tumor presence. This study compares the diagnostic accuracy of standard imaging and ADC/FET for detecting quantitatively assessment of tumor presence in diffuse glioma. METHODS Fifteen patients with newly diagnosed diffuse glioma were retrospectively included. Pre-operative MRI and FET PET imaging were available. Multiregional image-guided stereotactic biopsies were acquired before craniotomy. Quantitative imaging data from regions-of-interests (ROIs) centered at the biopsy locations was obtained. For each biopsy sample, semi-automatic cellularity and proliferation index, as well as DNA methylation-based tumor purity, was determined. Linear mixed models were used to evaluate which modalities were significant independent predictors for each tumor presence marker, and fitness was assessed using Bayesian Information Criterium. RESULTS 125 biopsies were analyzed (75 from eight high grade and 50 from seven low grade gliomas). Cellularity was associated with T1 weighted MRI (p = 0.033), ADC (p = 0.016) and ADC/FET (p &amp;lt; .001), with ADC/FET as best fit. ADC/FET was the only modality associated with proliferation index (p = 0.003) and with tumor purity (p &amp;lt; .001). CONCLUSION Combined ADC and FET PET is stronger associated with cellularity, proliferation index and tumor purity than standard MRI imaging. These findings may pave the way towards ADC/FET-guided local treatment of diffuse gliomas.
EPCO-06. THE EPIGENETIC CIRCUIT OF HOXDERNA LONG NON-CODING RNA (LNCRNA) ACTIVATES GLIOBLASTOMA-SPECIFIC TRANSCRIPTION PROGRAMS AND SUPER-ENHANCERS GENOME-WIDE, SHAPING GLIAL CELL FATE AND TRANSFORMATION
Authors: Evgeny Deforzh, Prakash Kharel, Pavel Ivanov, Anton Karelin, Erik Uhlmann, Anna Krichevsky
Journal: Neuro-Oncology (2023)

Abstract The origin and genesis of highly malignant and heterogeneous glioblastoma remain unknown. We have recently reported a unique enhancer-associated lncRNA (eRNA) LINC01116 (named here HOXDeRNA) that is silent in the normal brain but is commonly activated during gliomagenesis and controls gene expression in miR-10b/HOXD locus in cis by reshaping the locus topology. CRISPR activation experiments suggested that HOXDeRNA is sufficient to transform human astrocytes into glioma-like cells. Conversely, the knock-down of this lncRNA strongly impacts glioma viability. We now describe the global, genome-wide regulatory role of HOXDeRNA. Once expressed in normal cells of astroglial lineage, HOXDeRNA binds to histone methyltransferase EZH2 and removes Polycomb repression from hundreds of genes encoding glioma-specific transcription factors and other essential oncogenes across the entire genome (in trans). Among them are the core neurodevelopmental transcription factors SOX2, OLIG2, POU3F2, and SALL2. This results in the activation of glioma transcriptional programs and downstream super-enhancers enriched for binding sites of glioma master transcription factors SOX2 and OLIG2. Moreover, HOXDeRNA-induced astrocyte transformation is accompanied by the activation of multiple oncogenes, such as EGFR, PDGFR, and BRAF. We further identified a specific structure within the HOXDeRNA that mediates its genome-wide promoter binding and gene regulatory activity as a PRC2 decoy. These results have been obtained using the combination of ChIRP-Seq, ChIP-Seq, RNA-Seq, CLIP, CRISPR activation, and base editing, and intersect our analysis of normal and cancer cells with large public datasets. Thus, we describe the first lncRNA driving a cancer-specific transcriptional program globally, altering the epigenetic landscape across all 23 chromosome pairs, and resulting in the neoplastic transformation of normal cells to glioma. Overall, the results help reconstruct the sequence of events underlying the process of astrocyte transformation and suggest new RNA-targeting approaches for glioblastoma therapies.
CTNI-19. RESECTION AND CESIUM-131 RADIATION SOURCES IMBEDDED IN BIO-RESORBABLE COLLAGEN TILES (GAMMATILE™) FOLLOWED BY THE STUPP PROTOCOL IN NEWLY-DIAGNOSED GLIOBLASTOMA: GESTALT TRIAL-IN-PROGRESS UPDATE
Authors: Erin Dunbar, Adam Nowlan, David McCracken, Karen Fink, Luke Lewis, Mark Hoeprich, Stuart Lee, Anthony Paravati, Tolga Tuncer, John David, Divya Mella, Orwa Aboud, Ruben Fragoso, Orin Bloch, Clara Ferreira, Kathryn Dusenbery, Matthew Sean Peach, Eric Chang, David Brachman, Lisa Campbell, Clark Chen
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE To evaluate the safety and feasibility of combining resection with immediate initiation of radiation and subsequent Stupp protocol in newly-diagnosed glioblastoma (GBM). BACKGROUND Rapid early local progression (REP) after resection, prior to the initiation of EBRT+/-chemotherapy, occurs in 25-50%. This high-rate of REP supports initiation of an effective postoperative treatment as early as safely possible. Bio-resorbable collagen tiles with imbedded cesium-131 radiation sources (Gammatiles™) are FDA cleared for this use. Intraoperatively, tiles are placed within the resection bed, thus achieving an immediate initiation of surgically targeted radiation therapy (STaRT). DESIGN/ METHODS GESTALT is a single-arm 61 patient multi-center trial. Consented adults with suspected or confirmed GBM undergo a maximum safe resection with Gammatile™ (STaRT). Patients with molecular GBM (WHO 2021 criteria) start concurrent EBRT/Temozolomide beginning 25±4 days post-surgery. Subsequent EBRT (20 fractions, 4 weeks) to low and high-risk PTV takes Gammatile™ dose into account to a combined biologically equivalent dose of 46 and 60 Gy delivered in 2Gy/fraction, respectively. Adjuvant TMZ (6 cycles) begins 28±7 days after EBRT/Temozolomide. TTF is allowed. IDH-mutated gliomas are followed for safety. Outcomes include feasibility of incorporating Gammatile™ without delay of Stupp protocol, consent/attrition rates, safety, performance status trajectory (ECOG, KPS), immune competence (absolute lymphocyte counts), local control, PFS, and OS. RESULTS The trial opened in Fall 2022 at 4 sites. 12 additional sites are onboarding (NCT05342883). 16 patients are on trial as of abstract submission. Currently, this trial appears feasible and without any unexpected intolerances/toxicities. CONCLUSIONS This is the first trial in newly diagnosed GBM patients to combine resection, Gammatile™, and the Stupp protocol, in an attempt to reduce REP, as well as possibly, improve other outcomes. RESULTS will inform the routine and investigational use of Gammatile™, and if suggestive, will form the basis for a subsequent randomized trial.